Neurotrophins promote survival of many populations of neurons in the central nervous system and their deficiencies may play a pivotal role in the progression of neurodegenerative diseases. This application aims to examine the role of brain-derived neurotrophic factor (BDNF) in the pathogenesis of Huntington's disease (HD) in which striatal neurons are selectively lost. HD is caused by expansion of CAG repeats in the HD gene that encodes huntingtin. Striatal neurons express the BDNF receptor, TrkB, but do not express BDNF which mainly arrives at the striatum by anterograde transport from cortical neurons. Wild-type huntingtin induces, but mutant huntingtin inhibits, BDNF gene transcription in cortical neurons. Furthermore, mutant huntingtin has been shown to block axonal transport in fly and squid. This project will test the hypothesis that TrkB signaling is required for survival of striatal neurons and that the mutation in the HD gene reduces TrkB signaling by inhibiting expression and anterograde transport of BDNF, which, along with other deleterious effects of mutant huntingtin, leads to degeneration of striatal neurons. Mouse mutants in which the trkB gene is specifically deleted in the striatum will be used to examine whether TrkB signaling is required for survival of striatal neurons. The effect of mutant huntingtin on expression and anterograde transport of BDNF will be examined in HD transgenic mouse models. Two trkB mutant alleles will be used to produce HD transgenic mice that express TrkB at 100%, 50%, 24% or 12% of the normal amount, respectively. These mutant mice will then be used to determine whether striatal neurons expressing mutant huntingtin are more dependent on neurotrophic protection. Finally, the possibility that BDNF overexpression in cortical neurons delays the onset of HD will be investigated in HD and BDNF double transgenic mice. This research may lead to discovery of the BDNF-TrkB pathway as a promising target for designing effective treatments of Huntington's disease. [unreadable] [unreadable]